Increased intra anal pressures caused by hypertonicity of the internal anal sphincter (IAS) is associated with mucosal ischemia, ulceration, and severe pain in chronic anal fissure. Reduction of intra-anal pressure by surgical sphincterotomy is currently sued to promote symptomatic relief and healing of fissures, although the procedure can result in incontinence. The topical use of organic nitrates, e.g. nitroglycerin (NTG), presents a promising new approach to treat anal fissure. These powerful smooth muscle relaxants reduce intra-anal pressure, improve anodermal blood flow, relieve pain, and heal fissures in a majority of patients. However, the effectiveness of topical nitrate therapy is limited by systemic side effects such as headache, hypotension, and dizziness. The goal of this proposal is to pharmacologically enhance the potency of locally applied NTG to reduce anal pressure while minimizing systemic effects on blood pressure. To this end we will evaluate the ability of mechanistically different, topically applied spasmolytic agents to lower resting anal pressure, and to potentiate the local relaxant effects of NTG on the IAS of rats without affecting blood pressure. In addition, we will determine whether nitrate tolerance also limits the effectiveness of NTG in reducing intra-anal pressure, and whether other spasmolytic drugs can attenuate tolerance development. PROPOSED COMMERCIAL APPLICATIONS: There is a large market and unmet medical need for low cost topical alternatives to surgery for treading anal disease which affects 26 million people in the developed world (see page 19). This proposal will provide new therapies while improving efficacy and side effect profiles of nitroglycerin presently in a Phase III clinical trial for the treatment of anal fissure and subsequently for the treatment of thrombosed hemorrhoids and pain relief following hemrrhoidectomy.